title: Factors influencing plasma nevirapine levels: a study in HIV-infected children on generic antiretroviral treatment in India.
abstract: BACKGROUND
  Nevirapine is an important component of paediatric combination HIV therapy. Adequate drug exposure is necessary in order to achieve long-lasting viral suppression.
  
  
  OBJECTIVE
  To study the influence of age, drug dose and formulation type, nutritional status and CYP2B6 516G>T polymorphism on blood concentrations of nevirapine in children treated with generic antiretroviral drugs.
  
  
  METHODS
  A multicentre study was conducted at four sites in India. HIV-infected children receiving generic nevirapine-based fixed-dose combinations were recruited. Trough and 2 h nevirapine plasma concentrations were determined by HPLC. Characterization of the CYP2B6 gene polymorphism was performed using direct sequencing. Clinical and nutritional status was recorded. Groups were compared using the Mann-Whitney U-test and multivariable logistic regression analysis was performed to identify factors contributing to low drug levels.
  
  
  RESULTS
  Ninety-four children of median age 78 months were studied; 60% were undernourished or stunted. Stunted children had a significantly lower 2 h nevirapine concentration compared with non-stunted children (P < 0.05); there were no significant differences in trough concentrations between different nutritional groups. Nevirapine levels were significantly higher in children with TT compared with GG and GT CYP2B6 genotypes (P < 0.01). Children ≤ 3 years had a 3.2 (95% confidence interval 1.07-9.45) times higher risk of having sub-therapeutic nevirapine concentrations.
  
  
  CONCLUSIONS
  Nevirapine blood concentrations are affected by many factors, most notably age ≤ 3 years; a combination of young age, stunting and CYP2B6 GG or GT genotype could potentially result in sub-therapeutic nevirapine concentrations. Dosing recommendations for children should be reviewed in the light of these findings.
authors.affiliation: Tuberculosis Research Centre (Indian Council of Medical Research), Chennai, India. swaminathans@who.int
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Geetha
authors.initials: G
authors.lastname: Ramachandran
authors.forename: Hemanth Kumar
authors.initials: HK
authors.lastname: Agibothu Kupparam
authors.forename: Vasantha
authors.initials: V
authors.lastname: Mahalingam
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Soundararajan
authors.forename: Bhavani
authors.initials: B
authors.lastname: Perumal Kannabiran
authors.forename: Poorana Ganga Devi
authors.initials: PG
authors.lastname: Navaneethapandian
authors.forename: Ira
authors.initials: I
authors.lastname: Shah
authors.forename: Ramesh
authors.initials: R
authors.lastname: Karunaianandham
authors.forename: Rajasekaran
authors.initials: R
authors.lastname: Sikhamani
mesh_terms: D000367:Age Factors; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007194:India; D007223:Infant; D008297:Male; D015233:Models, Statistical; D019829:Nevirapine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D010949:Plasma / Q000737:chemistry*; D011110:Polymorphism, Genetic
chemical_list: D019380:Anti-HIV Agents; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating